The PI is a newly independent scientist (1R01DA029078-01A1) who is a physician and clinical researcher at Stanford University. This award will provide a period of intensive research focus that will allow the PI to enhance his research career (see RESEARCH). This award will also be used to foster the development of the candidate in order to expand his potential to make significant research contributions (see CANDIDATE). CANDIDATE: The PI is a newly independent scientist (1R01DA029078-01A1) with a history of previous NIH career development award funding (K23GM071400; NIH Clinical Research LRP), who will use the K02 award to pursue further career development activities in order to expand his potential to make significant research contributions. These activities include training in the responsible conduct of research, collaboration with senior researchers to develop new modes of inquiry, conference participation, further study proposals, research mentorship, and publication of quality research that translates directly to patient care. ENVIRONMENT: The PI's 400 sq. ft. human opioid physiology laboratory is situated in the Stanford School of Medicine, a hub of scientific activity and home to the 2008 and 2011 Center of Excellence-Winning Pain Management Center. The PI has active research collaborations with the Human Immune Monitoring Core and Lucas fMRI Imaging Center facilities at Stanford, in addition to ongoing relationships with senior scientists in the Epidemiology and Health Research Policy Departments. These facilities and collaborative relationships make Stanford an optimal environment to support the objectives of this award. RESEARCH: Currently, opioids are among the most common medications prescribed by physicians in the US and Vicodin (hydrocodone/acetaminophen) is the most prescribed medication of any category. However, physical dependence (PD), addiction, and opioid withdrawal (OW) complicate the use of prescription opioids. Among all Americans age 12 years and older in 2006, 13.6% (more than 33 million) reported having used prescription opioids for nonmedical purposes at least once, more than 12 million in the prior year, and 5.2 million in the prior month. Recent evidence from studies employing pharmacogenetic haplotype-based computational mapping have linked the 5HT3 receptor to PD and OW. Additional data from the PI's preliminary research show that 5HT3 receptor antagonists (RAs) can significantly decrease objective measures of opioid withdrawal in humans. The PI's current studies will evaluate the use of 5HT3-RAs for new indications in the treatment and prevention of prescription opioid drug abuse. Additional studies in the PI's lab aim to uncover the effects of chronic opioid therapy on human physiology through novel modalities, including fMRI and immunomodulation of opioid-induced changes. The implications of these research findings are substantial. By providing an effective, easily deliverable, low-cost method to mitigate the symptoms of OW and prevent the development or progression of PD, 5HT3-RA medications could drastically improve the treatment of pain.